Developmental brain injury is a major risk factor for neurological sequelae, including cognitive impairment, learning disability, Attention Deficit/Hyperactivity Disorder and cerebral palsy. Susceptibility to injury is especially high in prematurely born neonates. The cellular and physiological mechanisms underlying long-term consequences of premature birth on brain development are poorly understood, in particular damage to specific neural circuits. Diverse insults to the preterm brain contribute to injury, but little is known about the neurological effects of high tissue oxygen tension or hyperoxia (HO), which is associated with poor neurological outcome. Premature infants express lower levels of antioxidant enzymes than term infants, and lack adequate defenses against oxidative stress arising from the transition to increased oxygen tension at delivery. Our mouse model of perinatal HO-induced brain injury, using short-term exposure to high oxygen tension (80%) at P6-P8, shows delayed white matter development, disrupted integrity of axonal myelin, motor hyperactivity and impaired motor coordination. Learning disability and hyperactivity in survivors of preterm birth suggest damage to brain structures critical for memory formation. The hippocampus is a brain structure central to cognitive processing. As this brain region remains active in postnatal and adult neurogenesis, and in remodeling/synaptic plasticity, it is particulary vulnerable to insults. Our preliminary findings in the hippocampus indicate that perinatal HO generates reactive oxygen species, reduces parvalbumin- and GAD65-expressing interneuron populations, reduces GABA-ergic and disinhibits glutamatergic excitatory neurotransmission. These changes in neurotransmission, together with reduced adult dentate gyrus neurogenesis, are accompanied by adult memory and learning deficits. We therefore hypothesize that HO impairs the long-term capacity of the hippocampus for neurogenesis and remodeling, as well as development of specific hippocampal GABAergic circuitry. These changes disrupt the balance between excitatory and inhibitory (E/I) neurotransmission, which reduces synaptic plasticity and cognitive performance. Our proposed studies will test these hypotheses in two Specific Aims. In Aim 1, we will determine how HO attenuates the long-term neurogenic capacity of the hippocampus through cellular and gene expression changes. We will also perform electrophysiological studies to determine the effects of HO on disrupting E/I balance and the capacity for long-term potentiation. In Aim 2, we will define behavioral correlates of altered hippocampal remodeling, using tests of learning, memory and cognitive flexibility. Finally, we will determine whether pharmacological restoration of GABA neurotransmission improves E/I balance and cognitive performance following HO injury. Our study will establish functional relationships between HO-induced cellular changes, GABAergic interneuron dysfunction, long-term neurogenesis and cognitive deficits in a developmental model of neuronal injury. These will provide insights into injury mechanisms and functional readouts for future therapeutic intervention.